We propose to evaluate the impact of vitamin D3 (2,000 IU/day) and marine omega-3 fatty acids (1gm/d eicosapentaenoic acid [EPA]+840mg/d docosahexaenoic acid [DHA], in a 1.3:1 ratio), which have anti- inflammatory properties, on erythropoietic cell signaling and the development of anemia in the elderly in the setting of the newly launched VITamin D and OmegA-3 TriaL (VITAL). Anemia of any degree is recognized as a significant independent contributor to morbidity, mortality, and frailty in the elderly. Furthermore, race appears to be an important variable affecting anemia prevalence, with African-Americans displaying significantly higher rates of anemia than whites. As the number of elderly individuals is expected to reach unprecedented levels in the 21st century, anemia represents an emerging global health problem negatively impacting quality of life in the elderly population and requiring ever increasing allocation of health care resources. The pathogenesis of anemia in the elderly remains poorly studied and, as a consequence, there is a lack of proven preventive therapies. We recently showed that vitamin D deficiency is independently associated with a higher prevalence of anemia in the elderly, particularly among those with anemia of inflammation. We will take advantage of the VITAL study, a randomized, double-blind, placebo-controlled trial analyzing the role of vitamin D3 and marine omega-3 fatty acid (?-3 FA) supplements in the primary prevention of cancer and cardiovascular disease among 20,000 US men and women aged > 60 and > 65 years, respectively, to test the hypothesis that these interventions will ameliorate the development of anemia in the elderly. In addition, using a sub-sample of the VITAL cohort, we will investigate whether vitamin D and/or ?-3 FA influence erythropoiesis via hepcidin- and/or erythropoietin (EPO)-dependent pathways. We aim to determine whether vitamin D and/or w-3 FA supplements reduce the incidence of diagnosed anemia through the use of medical record review and supplementary questionnaires completed by participants' physicians. In our sub-study, fresh samples will be collected pre- and post-intervention from 900 subjects who will be evaluated at the Boston Clinical and Translational Science Center (CTSC). Using serial measurements of hemoglobin (HgB), red blood cell (RBC) indices, hepcidin, and erythropoietin, we will determine whether vitamin D and/or w-3 FA moderate inflammation-mediated effects on Hgb levels and erythropoietic pathways. The research infrastructure of the parent VITAL trial will provide a unique and cost-effective framework that will allow us to examine the potential benefits of vitamin D and/or w-3 FA supplementation in decreasing anemia in an elderly population. In order to complete baseline (pre-randomization) assessments of Hgb and erythropoietic pathways on fresh samples that will be collected from participants at the Boston CTSC site, it is critically important that this proposl begin in parallel to the 1-year enrollment period for the parent VITAL trial (1U01CA138962), scheduled to begin November 2011.